Antiphospholipid

Syndrome

Meredith Reyes, MD

10/15/2007

Antiphospholipid Syndrome

(APS)

1983 - Dr. Graham Hughes and his team in

London described “sticky blood”

Lupus patients had a tendency to blood clots,

headaches, strokes and, in pregnancy, clotting

of the placenta and miscarriage

These patients had “antiphospholipid antibody”

Recognized syndrome also occurred without

lupus

Mid 1990s – renamed “Hughes Syndrome”

Entity plagued by Misnomers

Antiphospholipid antibodies – antigen is a

protein that binds phospholipid

Lupus anticoagulant

Frequently found outside the clinical spectrum

of SLE

Prolong aPTT in vitro, but associated with a

hypercoagulable state in vivo

Antiphospholipid Syndrome

Primary APS

Occurs without underlying disease

Secondary APS

Occurs in the setting of underlying disease

SLE

Sjögren’s

Malignancy

Pathophysiology

“2-hit” hypothesis

Preexisting or coincident vascular damage

Antiphospholipid antibody May bind platelet phospholipids and promote

coagulation

May bind endothelial cell phospholipids and induce cell damage

May interfere with protein C, protein S and/or thrombomodulin function

aPTT

PT

aPTT & PT

Diagnostic Criteria for APS

One or more clinical criteria

One or more laboratory criteria

Clinical Criteria ≥ 1 episodes of venous, arterial or small vessel

thrombosis Deep vein thrombosis

Stroke/TIA

Pulmonary embolism

Superficial thrombophlebitis

Pregnancy morbidity Unexplained death at ≥ 10 weeks gestation of

morphologically normal fetus

≥ 1 premature births (< 34 weeks gestation) secondary to eclampsia, preeclampsia or placental insufficiency

≥ 3 pregnancy losses (<10 weeks gestation) unexplained by chromosomal, maternal anatomic or hormonal causes

Related clinical & laboratory

findings

Migraine headache

Raynaud phenomenon

Thrombocytopenia (50-140K)

Microangiopathic hemolytic anemia

Cutaneous ulcers

Livedo reticularis

Adrenal insufficiency

Pulmonary hypertension

Avascular necrosis

White matter lesions on MRI

Valvular heart disease – fibrin and platelet deposits

Thromboses

Venous > arterial

DVT & PE

More frequent with lupus anticoagulant

Antiphospholipid antibody in 5-21% of patients

Coronary, cerebrovascular and peripheral arterial events

More frequent with anticardiolipin antibodies

Catastrophic Antiphospholipid

Syndrome

Rare

Multiorgan failure

Due to widespread thrombotic disease

+ DIC panel

Frequently fatal (50% mortality)

Antiphospholipid Antibodies

1-15% of the general population

50-70% of patients with SLE

Frequency of APS much lower!

Transient antibodies

Laboratory Criteria

Antiphospholipid antibodies

Lupus anticoagulant

Anticardiolipin antibodies

Anti-β2 glycoprotein I antibodies

Two or more occasions at least 12 weeks apart

No more than five years prior to clinical

manifestations

Lupus Anticoagulant (LA)

Prolongs phospholipid dependent coagulation tests Activated partial thromboplastin time (aPTT)

PT rarely affected – reagent contains high concentration of phospholipid

Undefined epitopes

50% of patients with LA meet criteria for SLE

Can be associated with medications – quinidine, procainamide, chlorpromazine

With LA ~30% risk of developing APS symptoms

Clotting assays All testing performed with platelet poor plasma

Evaluation of lupus anticoagulant

Step 1: Test for prolongation of

coagulation in ≥ 1 phospholipid dependent

in vitro coagulation assay

Laboratory Evaluation of LA PTT-LA

Reduced amount of phospholipid present

Dilute Russell Viper Venom Time (dRVVT) Russell Viper Venom directly activates factor X

(common pathway) Phospholipid dependent

More sensitive than the aPTT test Not influenced by deficiencies or inhibitors of clotting factors

VIII, IX or XI

dRVVT reagent is diluted to ensure that it has a low phospholipid concentration, increasing the sensitivity for LA Patient without LA will clot in 36-42 seconds

Patient with LA will have prolonged clotting

Must use platelet poor plasma

Contains heparin inhibitor (Hepzyme)

Normal plasma

dRVVT 36-42 sec

Plasma with lupus anticoagulant

dRVVT > 43 sec

Dilute Russell Viper

Venom Time

Phospholipid

Evaluation of lupus anticoagulant

Step 2: Mixing studies

Mix equal parts patient and control plasma

aPTT will correct if prolongation due to factor

deficiencies

If LA present will fail to correct aPTT

Clotting time > 5 seconds longer than control

plasma alone

Usually immediate acting

Evaluation of lupus anticoagulant

Step 3: Neutralization study

Addition of phospholipid will neutralize lupus

anticoagulant

Measured aPTT will become shortened

Platelet neutralization

Lysates of frozen, thawed and washed platelets

Hexagonal phase phospholipid neutralization

LA Confirmatory Tests

Platelet Neutralization Sta Clot-LA

Prolonged aPTT Shortened aPTT Shortened aPTT Prolonged aPTT

Clotting time >8 seconds shorter after addition of PL = + for LA

Evaluation of lupus anticoagulant

Step 4: Rule out other coagulopathies

Specific factor assays

With LA, factor activity appears to increase with

increasing dilutions of plasma

Diluting lupus anticoagulant

Anticardiolipin antibodies

May occur with infections or medications These are rarely of clinical significance

May be Β2-glycoprotein I dependent Usually those found in autoimmune disease

Not those antibodies formed secondary to infection

May behave like a lupus anticoagulant in in vitro testing

Alone, may not be a risk factor for thrombosis

Presence is a risk factor for recurrence of thromboembolic events

Measure via ELISA IgG, IgM or IgA

+ if medium/high titer >40 GPL or MPL or >99th percentile

Β2-Glycoprotein I Antibodies

Most common target of APA

Found in patients with APS and positive

anticardiolipin antibodies

Without anti-β2-GP-I may not have increased

clotting risk

Not present with antibodies formed secondary

to infection

Other Antibodies

Anti-prothrombin

Anti-annexin V

Anti-phosphatidylserine

Anti-phosphatidylinositol

Associated with APS

Clinical role poorly understood

Thrombotic Risk

In patients with APS:

Thrombosis rate ~2.4%/year

Thrombosis risk ↑ 6-10X

10-15%/year recurrence rate without

anticoagulation therapy

In secondary APS, ongoing vasculitis =

continual risk for thrombosis

Venereal Disease Research

Laboratory (VDRL)

Serologic test for syphilis

Measures agglutination of lipid particles

containing cholesterol and cardiolipin

Antiphospholipid antibodies may bind and

cause agglutination False + VDRL

Occurs in ½ of patients with APS

Treatment

After venous thrombosis: Heparin followed by Coumadin

Highest risk of recurrence in first 6-12 months

After arterial thrombosis: Aspirin +/- coumadin

Secondary APS: Aspirin, hydroxychloroquine, pentoxifylline, coumadin or LMW

Heparin

Catastrophic APS: Aspirin, coumadin, corticosteroids, plasmapheresis, IVIG

Pregnancy Aspirin +/- prednisone

References

Henry’s Clinical Diagnosis and Management by Laboratory Methods

Uptodate.com

Garcia DA, et al. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: A case-based review. Blood. Online July 20, 2007

Giannakopoulos B, et al. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood; 15 Jan 2007 (109)2; 422-30.

Galli M, et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood; 1 March 2003 (101)5; 1827-32.